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@ARTICLE{MorenasRodrguez:163733,
author = {Morenas-Rodríguez, Estrella and Li, Yan and Nuscher,
Brigitte and Franzmeier, Nicolai and Xiong, Chengjie and
Suarez-Calvet, Marc and Fagan, Anne M and Schultz, Stephanie
and Gordon, Brian A and Benzinger, Tammie L S and
Hassenstab, Jason and McDade, Eric and Feederle, Regina and
Karch, Celeste M and Schlepckow, Kai and Morris, John C and
Kleinberger, Gernot and Nellgard, Bengt and Vöglein,
Jonathan and Blennow, Kaj and Zetterberg, Henrik and Ewers,
Michael and Jucker, Mathias and Levin, Johannes and Bateman,
Randall J and Haass, Christian and Adams, Sarah and Allegri,
Ricardo and Araki, Aki and Barthelemy, Nicolas and Bechara,
Jacob and Berman, Sarah and Bodge, Courtney and Brandon,
Susan and Brooks, William Bill and Brosch, Jared and Buck,
Jill and Buckles, Virginia and Carter, Kathleen and Cash,
Lisa and Chen, Charlie and Chhatwal, Jasmeer and Chrem,
Patricio and Chua, Jasmin and Chui, Helena and Cruchaga,
Carlos and Day, Gregory S and De La Cruz, Chrismary and
Denner, Darcy and Diffenbacher, Anna and Dincer, Aylin and
Donahue, Tamara and Douglas, Jane and Duong, Duc and Egido,
Noelia and Esposito, Bianca and Farlow, Marty and Feldman,
Becca and Fitzpatrick, Colleen and Flores, Shaney and Fox,
Nick and Franklin, Erin and Friedrichsen, Nelly and Fujii,
Hisako and Gardener, Samantha and Ghetti, Bernardino and
Goate, Alison and Goldberg, Sarah and Goldman, Jill and
Gonzalez, Alyssa and Gräber-Sultan, Susanne and
Graff-Radford, Neill and Graham, Morgan and Gray, Julia and
Gremminger, Emily and Grilo, Miguel and Groves, Alex and
Häsler, Lisa and Hellm, Cortaiga and Herries, Elizabeth and
Hoechst-Swisher, Laura and Hofmann, Anna and Holtzman, David
and Hornbeck, Russ and Igor, Yakushev and Ihara, Ryoko and
Ikeuchi, Takeshi and Ikonomovic, Snezana and Ishii, Kenji
and Jack, Clifford and Jerome, Gina and Johnson, Erik and
Kaeser, Stephan and Kasuga, Kensaku and Keefe, Sarah and
Klunk, William Bill and Koeppe, Robert and Koudelis, Deb and
Kuder-Buletta, Elke and Laske, Christoph and Levey, Allan
and Lopez, Oscar and Marsh, Jacob and Martinez, Rita and
Martins, Ralph and Mason, Neal Scott and Masters, Colin and
Mawuenyega, Kwasi and McCullough, Austin and Mejia, Arlene
and MountzMD, James and Mummery, Cath and Nadkarni, Neelesh
and Nagamatsu, Akemi and Neimeyer, Katie and Niimi, Yoshiki
and Noble, James and Norton, Joanne and Nuscher, Brigitte
and O'Connor, Antoinette and Obermüller, Ulricke and
Patira, Riddhi and Perrin, Richard and Ping, Lingyan and
Preische, Oliver and Renton, Alan and Ringman, John and
Salloway, Stephen and Schofield, Peter and Senda, Michio and
Seyfried, Nick and Shady, Kristine and Shimada, Hiroyuki and
Sigurdson, Wendy and Smith, Jennifer and Smith, Lori and
Snitz, Beth and Sohrabi, Hamid and Stephens, Sochenda and
Taddei, Kevin and Thompson, Sarah and Wang, Peter and Wang,
Qing and Weamer, Elise and Xu, Jinbin and Xu, Xiong},
collaboration = {Network, Dominantly Inherited Alzheimer},
title = {{S}oluble {TREM}2 in {CSF} and its association with other
biomarkers and cognition in autosomal-dominant {A}lzheimer's
disease: a longitudinal observational study.},
journal = {The lancet / Neurology},
volume = {21},
number = {4},
issn = {1474-4422},
address = {London},
publisher = {Lancet Publ. Group},
reportid = {DZNE-2022-00472},
pages = {329 - 341},
year = {2022},
note = {(CC BY-NC-ND)},
abstract = {Therapeutic modulation of TREM2-dependent microglial
function might provide an additional strategy to slow the
progression of Alzheimer's disease. Although studies in
animal models suggest that TREM2 is protective against
Alzheimer's pathology, its effect on tau pathology and its
potential beneficial role in people with Alzheimer's disease
is still unclear. Our aim was to study associations between
the dynamics of soluble TREM2, as a biomarker of TREM2
signalling, and amyloid β (Aβ) deposition, tau-related
pathology, neuroimaging markers, and cognitive decline,
during the progression of autosomal dominant Alzheimer's
disease.We did a longitudinal analysis of data from the
Dominantly Inherited Alzheimer Network (DIAN) observational
study, which includes families with a history of autosomal
dominant Alzheimer's disease. Participants aged over 18
years who were enrolled in DIAN between Jan 1, 2009, and
July 31, 2019, were categorised as either carriers of
pathogenic variants in PSEN1, PSEN2, and APP genes (n=155)
or non-carriers (n=93). We measured amounts of cleaved
soluble TREM2 using a novel immunoassay in CSF samples
obtained every 2 years from participants who were
asymptomatic (Clinical Dementia Rating [CDR]=0) and annually
for those who were symptomatic (CDR>0). CSF concentrations
of Aβ40, Aβ42, total tau (t-tau), and tau phosphorylated
on threonine 181 (p-tau) were measured by validated
immunoassays. Predefined neuroimaging measurements were
total cortical uptake of Pittsburgh compound B PET
(PiB-PET), cortical thickness in the precuneus ascertained
by MRI, and hippocampal volume determined by MRI. Cognition
was measured using a validated cognitive composite
(including DIAN word list test, logical memory delayed
recall, digit symbol coding test [total score], and
minimental status examination). We based our statistical
analysis on univariate and bivariate linear mixed effects
models.In carriers of pathogenic variants, a high amyloid
burden at baseline, represented by low CSF Aβ42 (β=-4·28
× 10-2 [SE 0·013], p=0·0012), but not high cortical
uptake in PiB-PET (β=-5·51 × 10-3 [0·011], p=0·63), was
the only predictor of an augmented annual rate of subsequent
increase in soluble TREM2. Augmented annual rates of
increase in soluble TREM2 were associated with a diminished
rate of decrease in amyloid deposition, as measured by Aβ42
in CSF (r=0·56 [0·22], p=0·011), in presymptomatic
carriers of pathogenic variants, and with diminished annual
rate of increase in PiB-PET (r=-0·67 [0·25], p=0·0060) in
symptomatic carriers of pathogenic variants. Presymptomatic
carriers of pathogenic variants with annual rates of
increase in soluble TREM2 lower than the median showed a
correlation between enhanced annual rates of increase in
p-tau in CSF and augmented annual rates of increase in
PiB-PET signal (r=0·45 [0·21], p=0·035), that was not
observed in those with rates of increase in soluble TREM2
higher than the median. Furthermore, presymptomatic carriers
of pathogenic variants with rates of increase in soluble
TREM2 above or below the median had opposite associations
between Aβ42 in CSF and PiB-PET uptake when assessed
longitudinally. Augmented annual rates of increase in
soluble TREM2 in presymptomatic carriers of pathogenic
variants correlated with decreased cortical shrinkage in the
precuneus (r=0·46 [0·22]), p=0·040) and diminished
cognitive decline (r=0·67 [0·22], p=0·0020).Our findings
in autosomal dominant Alzheimer's disease position the TREM2
response within the amyloid cascade immediately after the
first pathological changes in Aβ aggregation and further
support the role of TREM2 on Aβ plaque deposition and
compaction. Furthermore, these findings underpin a
beneficial effect of TREM2 on Aβ deposition, Aβ-dependent
tau pathology, cortical shrinkage, and cognitive decline.
Soluble TREM2 could, therefore, be a key marker for clinical
trial design and interpretation. Efforts to develop
TREM2-boosting therapies are ongoing.German Research
Foundation, US National Institutes of Health.},
keywords = {Adult / Alzheimer Disease: diagnostic imaging / Alzheimer
Disease: genetics / Amyloid beta-Peptides / Biomarkers /
Cognition: physiology / Cognitive Dysfunction: diagnostic
imaging / Cognitive Dysfunction: genetics / Humans /
Membrane Glycoproteins: cerebrospinal fluid / Membrane
Glycoproteins: genetics / Middle Aged / Receptors,
Immunologic: genetics / United States / Amyloid
beta-Peptides (NLM Chemicals) / Biomarkers (NLM Chemicals) /
Membrane Glycoproteins (NLM Chemicals) / Receptors,
Immunologic (NLM Chemicals) / TREM2 protein, human (NLM
Chemicals)},
cin = {AG Haass / Ext LMU / AG Feederle / AG Herms / AG Höglinger
1 / AG Simons / AG Jucker / AG Levin},
ddc = {610},
cid = {I:(DE-2719)1110007 / I:(DE-2719)5000048 /
I:(DE-2719)1140004 / I:(DE-2719)1110001 / I:(DE-2719)1110002
/ I:(DE-2719)1110008 / I:(DE-2719)1210001 /
I:(DE-2719)1111016},
pnm = {352 - Disease Mechanisms (POF4-352) / 353 - Clinical and
Health Care Research (POF4-353) / 351 - Brain Function
(POF4-351)},
pid = {G:(DE-HGF)POF4-352 / G:(DE-HGF)POF4-353 /
G:(DE-HGF)POF4-351},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:35305339},
pmc = {pmc:PMC8926925},
doi = {10.1016/S1474-4422(22)00027-8},
url = {https://pub.dzne.de/record/163733},
}
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